Immunity refers to self-protective action from foreign substances by recognizing and removing foreign antigenic substances existing in the body. Immune response can be largely divided into cell-mediated immune response and humoral immune response. In humoral immune response, antibodies secreted by B cells recognize foreign antigens and neutralize them, help phagocytosis of macrophages by binding to the surface of other cells recognized as being non-self, or augment specific immune response by activating the complement system. In cell-mediated immune response, cytotoxic T cells (Tc cells) directly inactivate foreign antigens or activate macrophages by secreting cytokines such as IL-2 and IFN-gamma. As such, in immune response, the ability to discriminate between self and non-self antigen is absolutely important.
However, in a specific situation of transplantation of allogeneic or xenogeneic cells, tissues or organs, it is necessary to suppress immune response to prevent rejection of beneficial foreign graft. For example, to treat blood cancers such as leukemia, myeloma, lymphoma and aplastic anemia, allogeneic bone marrow transplant or hematopoietic stem cell transplant has been used as an effective treatment method. However, in the case of immune rejection response by recognizing a host as non-self antigen, the graft derived from a donor may cause damage to tissue, skin, organ and the like of a recipient, and even death in the worst case. As such, a disease in which a graft damages tissues of a host by causing immune rejection response is called graft-versus-host disease (GVHD). For example, in the case of stem cell transplant, it refers that new cells (graft) transplanted to bone marrow recognize the tissues of the patient (host) as foreign so that the stem cells of the allogeneic donor damage tissue, skin, digestive organ, or organ such as liver and the like of the recipient. In the pathogenesis of graft-versus-host disease, antigen-presenting cells of the patient activate T cells among transplanted bone marrow cells to differentiate into Th1 cells and increase the secretion of cytokines such as IL-2 and IFN-gamma, thereby activating cytotoxic T cells and natural killer cells, and they attack the organs of the patient to cause graft-versus-host disease. The major cause of graft-versus-host disease is allogeneic bone marrow transplant or hematopoietic stem cell transplant. Specifically, it has been reported that graft-versus-host disease is caused by hematopoietic stem cell transplant and 15-30% of the patients died. Therefore, to prevent occurrence of graft-versus-host disease and to ensure that graft survives for a long time, the immune system of the recipient that recognize foreign antigen should be evaded or the immune response should be suppressed.
In addition, in immune hypersensitivity reaction such as allergic reaction, in the case that the immunological reaction of a subject causes larger damage than invading foreign substances, suppression of immune reaction is necessary. Examples of such allergic diseases are allergic rhinitis, asthma, atopic dermatitis and the like. Furthermore, autoimmune diseases refer to a disease in which the immune system is to overly sensitive to the part of the subject's body so that the capacity of discriminating the self from the non-self is defective, destroying its own body. Autoimmune diseases also need treatment for suppressing immune response. Examples of such autoimmune diseases are rheumatic arthritis, insulin-dependent diabetes mellitus, multiple sclerosis, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, myasthenia gravis, polymyositis, dermatomyositis, autoimmune cytopenias, vasculitis syndrome, systemic lupus erythematosus and the like. All over the world, diseases caused by immune hypersensitivity reaction have been increased, but the root cause for such diseases has not been sufficiently investigated. Therefore, suppression of immune reaction has been widely used as a useful therapy for the treatment of patients suffering from immune diseases such as transplant rejection, graft-versus-host disease, allergic disease and autoimmune disease. At present, many chemical immunosuppressants for suppression of immune reaction have been developed, and cyclosporin A showed the best clinical effect and has been widely used for autoimmune diseases including graft-versus-host disease, transplant rejection and various inflammatory diseases. When cyclosporin A is used at high doses, it completely suppresses the activation of T cells to treat diseases, but has the disadvantage of showing considerable side effects including kidney toxicity. Therefore, it is recommended to use at low doses. In addition, to help overcome reduced medicinal effect due to low-dose use, administration in combination with 2 or 3 other immunosuppressants has been carried out. However, for co-administration, there is a prerequisite that the mechanism of action and the toxicity site of two compounds are different. Therefore, there is a need to develop more effective immunosuppressant which can replace conventional immunosuppressants.
Meanwhile, T cells—one of the cell groups that play a central role in the immune system—mature in the thymus and are classified into CD4-positive helper T cell (Th cell) and CD8-positive cytotoxic T cell. Via a series of differentiation procedures, helper T cells differentiate into T cells having intrinsic properties—Th1 (T helper type 1), Th2 (T helper type 2), Th17 (T helper type 17), regulatory T cell (Treg cell) and the like. Regulatory T cell has a property of controlling inflammatory reaction by suppressing the function of abnormally activated immune cells, so that it has been known that immune diseases can be treated by the action of increasing activity of regulatory T cell. Regulatory T cell uses CD4+CD25+ as a marker and expresses transcription factor Foxp3. The importance of regulatory T cell in immune tolerance and autoimmune diseases is evident in scurfy mouse which has Foxp3 mutation. Scurfy mouse having Foxp3 mutation dies only a month after birth due to excessive activation of CD4+ T cells and excessive production of inflammatory cytokines (Sakaguchi S. et al., Cell 2008, 133:775-787), and in humans it is the cause of Foxp3 gene mutation hereditary disease, IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) which causes many autoimmune diseases such as diabetes mellitus type 1, allergy, inflammatory bowel disease and the like (Itoh M. et al., J Immunol 1999, 162:5317-5326). Therefore, it can be expected that various immune diseases including autoimmune diseases and chronic inflammatory diseases can be treated by activating regulatory T cells or administering a medication having regulatory T cells as an active ingredient. However, regulatory T cells are differentiated cells having immunosuppressive function as compared with other T lymphocytes produced from the thymus, and they are already stimulated by self-antigen in the thymus. Regulatory T cells are comprised of about 5% of thymus T lymphocytes, and about 10-15% of CD4+ T lymphocytes exist in the end-organ. As a result, it is very difficult to obtain a therapeutically effective amount of regulatory T cells, and a method for obtaining a large number of regulatory T cells effectively is desired.
Meanwhile, Korean Patent Application Publication No. 10-2009-0018593 provides novel indole or indazole compounds having activity of inhibiting cellular necrosis and a therapeutic agent for the treatment of necrosis-associated diseases comprising thereof. However, the above patent document discloses the activity of the above indole or indazole compounds on inhibiting cellular necrosis and association with some necrosis-associated diseases such as hepatic disease, neurodegenerative disease and the like only, and never mentions an association of the above compounds with regulatory T cells, the efficacy on suppressing immune response or the possibility of being used in the treatment of immune hypersensitivity reaction-associated diseases.
Accordingly, the present inventors sought to provide compounds having excellent immunosuppressive efficacy which can replace or assist conventional immunosuppressants. As a result, the present inventors found that the compounds of Korean Patent Application Publication No. 10-2009-0018593, specifically (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1H-indol-7-yl]amine—which is known as a cellular necrosis inhibitor promotes differentiation from immature T cells into regulatory T cells and proliferation and shows excellent immunosuppressive efficacy, and thus can be widely applied to the treatment of transplant rejection, graft-versus-host disease, allergic diseases, autoimmune diseases and the like to accomplish the present invention.